5-35644519-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024867.4(SPEF2):c.579T>C(p.Ile193=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.666 in 1,591,038 control chromosomes in the GnomAD database, including 356,525 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (37557 hom., cov: 32)
  • Exomes 𝑓: 0.66 (318968 hom.)
• Consequence: SPEF2 NM_024867.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.13

Genes affected

SPEF2 (HGNC:26293): (sperm flagellar 2) Involved in sperm axoneme assembly. Located in sperm flagellum. Implicated in spermatogenic failure 43. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 5-35644519-T-C is Benign according to our data. Variant chr5-35644519-T-C is described in ClinVar as [Benign]. Clinvar id is 403472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.13 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.847 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPEF2	NM_024867.4	c.579T>C	p.Ile193=	synonymous_variant	4/37	ENST00000356031.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPEF2	ENST00000356031.8	c.579T>C	p.Ile193=	synonymous_variant	4/37	1	NM_024867.4	P2

Frequencies

GnomAD3 genomes AF: 0.698 AC: 106056 AN: 151918 Hom.: 37496 Cov.: 32

Gnomad AFR AF: 0.774

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.725

Gnomad ASJ AF: 0.660

Gnomad EAS AF: 0.869

Gnomad SAS AF: 0.826

Gnomad FIN AF: 0.609

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.643

Gnomad OTH AF: 0.674

GnomAD3 exomes AF: 0.707 AC: 162203 AN: 229368 Hom.: 58134 AF XY: 0.703 AC XY: 87402 AN XY: 124254

Gnomad AFR exome AF: 0.779

Gnomad AMR exome AF: 0.794

Gnomad ASJ exome AF: 0.663

Gnomad EAS exome AF: 0.866

Gnomad SAS exome AF: 0.815

Gnomad FIN exome AF: 0.628

Gnomad NFE exome AF: 0.641

Gnomad OTH exome AF: 0.680

GnomAD4 exome AF: 0.663 AC: 953405 AN: 1439002 Hom.: 318968 Cov.: 33 AF XY: 0.666 AC XY: 476156 AN XY: 715286

Gnomad4 AFR exome AF: 0.779

Gnomad4 AMR exome AF: 0.781

Gnomad4 ASJ exome AF: 0.659

Gnomad4 EAS exome AF: 0.875

Gnomad4 SAS exome AF: 0.810

Gnomad4 FIN exome AF: 0.633

Gnomad4 NFE exome AF: 0.637

Gnomad4 OTH exome AF: 0.678

GnomAD4 genome AF: 0.698 AC: 106183 AN: 152036 Hom.: 37557 Cov.: 32 AF XY: 0.699 AC XY: 51961 AN XY: 74298

Gnomad4 AFR AF: 0.775

Gnomad4 AMR AF: 0.725

Gnomad4 ASJ AF: 0.660

Gnomad4 EAS AF: 0.868

Gnomad4 SAS AF: 0.826

Gnomad4 FIN AF: 0.609

Gnomad4 NFE AF: 0.643

Gnomad4 OTH AF: 0.677

Alfa AF: 0.652 Hom.: 52204

Bravo AF: 0.707

Asia WGS AF: 0.830 AC: 2886 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

- -

Spermatogenic failure 43 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
Cadd	Benign	0.36
Dann	Benign	0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs7706444; hg19: chr5-35644621;